Project Summary/Abstract The goal of this project is to develop a therapeutic product that relieves chemotherapy-induced peripheral neuropathy (CIPN) in a non-permanent, non-addictive and long lasting manner to improve the quality of life of cancer patients. Currently more than 100 million Americans and 1.5 billion people worldwide suffer from chronic pain. Voltage-gated sodium channels transmit pain signals in nociceptive neurons. Nine genes have been identified, each having unique properties and tissue distribution patterns. Genetic studies have correlated a rare hereditary loss-of-function mutation in one channel isoform ? NaV1.7 ? with a genetic disorder known as Congenital Insensitivity to Pain (CIP). Individuals with CIP are not able to feel pain whatsoever and they do not present any significant secondary alteration. Thus, selective repression of NaV1.7 should recapitulate the phenotype of CIP. However, the high homology of human NaV proteins, have frustrated most efforts to develop selective inhibitors. We have developed a non-permanent gene therapy to target pain that is non-addictive (because it targets a non-opioid pathway), highly specific (only targeting the gene of interest), and long-term lasting (around 3 weeks in our preliminary assays in mice). During this Phase I SBIR, we will 1) optimize the in vitro targeting of NaV1.7 along with targeting NaV1.8 and NaV1.9, since these channels are also responsible for the transmission of pain signals, 2) evaluate the new targets in vivo in a chemotherapy-induced peripheral neuropathy (CIPN) model and determine whether there are any sex differences in efficacy of the therapeutic, and 3) perform preliminary safety and toxicology studies in mice. At the end of Phase I, we will know the potency, specificity, and safety of our optimized gene therapy and will apply for a Phase II SBIR grant to perform IND-enabling toxicology studies. Our goal is to advance this therapy forward into the clinic, to provide an alternative treatment to opioids for cancer patients in pain.